Pramipexole Augmentation to Target Anhedonia in Depression - a Pilot Study
Phase: PHASE2
Conditions: Depression, Bipolar, Depression, Unipolar, Dysthymia, Anhedonia
Sponsor: Region Skane

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1 T ITEL   
Adjunctive Treatment With Pramipexole 
for Anhedonia Symptoms in Depression – 
A Pilot Study (PILOT-PRAXOL)   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study protocol    
Version: 1.1  
Dated: 2019-06-17  
 
 
 
 
 
EudraCT: 2019-001907-19 
ClinicalTrails.gov ID: NCT04121091  
 
 
 
 
 
Sponsor: Region Skåne through Adult Psychiatry Clinic, Lund.  
Principal Investigator: Daniel Lindqvist.   
 
 

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2 SIGNATURE   
 
 
I have read this protocol and it contains all the essential elements to carry out the study. By signing the 
study, I agree to conduct the study in all its parts according to this protocol, the informed consent, and 
to comply with ICH GCP, the Declaration of Helsinki and the national and international regulations that 
apply to the clinical study in question.   
I will share the protocol and any other important study-related information with my co-workers in order 
for them to conduct the study properly. I am aware of my responsibility to keep the employees working 
on the study informed and educated.   
I understand that any information provided to me in connection with this study that has not 
previously been published is considered confidential information.   
 
 
 
 
…………………………………………………………………………………………………………………………. 
Signature of the principal investigator  
Daniel Lindqvist  
Psychiatry Skåne VO Psychiatry Lund  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PILOT-PRAXOL /EudraCT version 
1.1_2019-06-17  

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3  
 
 
 
 
 
ABBREVIATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3T MR  
3 Tesla magnetic resonance imaging  
AE  
Adverse Event/Incident – unwanted medical event  
AES  
The Apathy Evaluation Scale  
BOLD  
Blood-oxygen-level dependent imaging  
CRF  
Case Report Form  
CRP  
C-reactive Protein  
D3  
receptor  
D3 dopamine receptor  
DARS  
Dimensional Anhedonia Rating Scale  
DSF  
European Union General Data Protection Regulation (EU 2016/679) (GDPR)  
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders 5 ed.  
eCRF  
Electronic Case Report Form  
ECT  
Electroconvulsive therapy  
eGFR  
Estimated glomerular filtration rate  
EU 
European Union  
Eu CTR  
EU Clinical Trials Register  
FASS 
Pharmaceutical Specialties in Sweden  
fMRI  
Functional magnetic resonance imaging  
GAD-7  
Generalized Anxiety Disorder-7  
GCP  
Good Clinical Practice  
Hb  
Hemoglobin  
ICD-10  
International Statistical Classification of Diseases and Related Health Problems 10 ed.  
ICH 
International Council for Harmonisation  
ICMJE  
International Committee of Medical Journal Editors  
IL 
Interleukin  
Source data  Any information in original and certified copies of original documents of clinical 
findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the study.   The source data is contained in source 
documents (original or certified copies). (ICH-GCP E6)   

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LPT  
The Act on Compulsory Psychiatric Care  
LV  
Swedish Medical Products Agency  
LVFS  
2011:19  
Guidance to the Medical Products Agency's regulations on clinical trials of medicinal 
products in humans   
MADRS  
Montgomery-Åsberg Depression Rating Scale  
MAOIs  
Monoamine oxidase inhibitors  
MAP-SR  
Motivation and Pleasure Scale – Self-Report  
MID-task  
Monetary Incentive Delay task   
MINI  
Mini International Neuropsychiatric Interview  
Monitor  
An independent person who reviews that the study is conducted, documented, and 
reported in accordance with approved study protocols, Standard Operating 
Procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory 
requirements.   
NAc  
Nucleus accumbens  
PAL  
Patient-responsible doctor at a psychiatric ward or health center  
 PoC 
Proof-of-Concept  
Investigat
or  
A licensed physician or licensed dentist performing 
trial at a trial site 
 
  
PS  
Parkinson's disease  
EPM  
The Ethical Review Authority  
RCT  
Randomized controlled trial  
SAE  
Serious Adverse Event – serious unwanted medical event  
SD  
Standard Deviation  
SHAPS  
Snaith–Hamilton Pleasure Scale  
SmPC  
Summary of Product Characteristics - a document written by the manufacturer at the 
time of registration of a medicinal product and is a summary of the characteristics and 
use of the medicinal product.   
SSRI  
Selective serotonin reuptake inhibitors  
SUAS 
Suicide Assessment Scale  
SUS  
Skåne University Hospital  
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TNF  
Tumor Necrosis Factor  
YMRS 
Young Mania Rating Scale 

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4 CONTACT INFORMATION  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Role in the study   
Name and title  
Contact information:  
Sponsor and PI 
 
Daniel Lindqvist; Associate 
Professor, Physician 
Address: Adult Psychiatry Lund, Baravägen  
1, 222 40 Lund  
E-mail: daniel.lindqvist@med.lu.se  
Phone: 046-173885   
Investigator  
Filip Ventorp; PhD, MD   
   
Address: Adult Psychiatry Lund, 
Baravägen 1, 222 40 Lund   
E-mail: filip.ventorp@med.lu.se  
Phone: +46 72 302 888 2   
Investigator  
Johan Lindelin; Heal   
   
Address: Adult Psychiatry Lund, 
Baravägen 1, 222 40 Lund   
E-mail: johan.lindelin@med.lu.se  
Phone: +46 70 36477 45   
Research Nurse  
Linda Hansson   
Address: Adult Psychiatry Lund, 
Baravägen 1, 222 40 Lund   
E-mail: Linda.MM.Hansson@skane.se  
Phone: 046-174801   
Head of Adult 
Psychiatry, Lund  
for  Eva-Lena Brönmark   
Address: Adult Psychiatry Lund, 
Baravägen 1, 222 40 Lund   
E-mail: eva-lena.bronmark@skane.se  
Phone: 046 - 17 40 18   
Monitor  
Clinical  studies  Sweden  -   Address: Skåne University Hospital,  
221 85 Lund  
Forum South  

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5  
 
 
 
 
 
SYNOPSIS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsors Protocol ID  
1.1 20190619 
Title 
Adjunctive treatment with Pramipexole for Anhedonia Symptoms in 
Depression – A Pilot Study 
EudraCT nr.  
2019-001907-19  
Background and expected 
benefits  
The majority of depressed patients do not achieve remission with 
current treatment methods. Many continue to suffer from severe 
residual symptoms of anhedonia – the inability to experience 
pleasure and a reduced sense of drive – after treatment. At present, 
there is no specific and effective treatment available for anhedonia. 
Pramipexole, a dopamine agonist used in Parkinson’s disease, has 
been shown to be effective against anhedonic symptoms in that 
condition. Clinical experience has also demonstrated treatment 
effects of high-dose pramipexole in treatment-resistant depression; 
however, randomized clinical trials have only been conducted with 
low-dose pramipexole and have not specifically examined its effects 
on anhedonia. This pilot study is expected to serve as a basis for a 
larger placebo-controlled randomized treatment trial of high-dose 
pramipexole as an adjunctive therapy in depression with severe 
anhedonic symptoms. 
Objective  
Primary question: Do anhedonia symptoms, as assessed by the 
Dimensional Anhedonia Ration Scale (DARS) self-assessment 
questionnaire, decrease after 10 weeks of additional treatment with 
pramipexole?   
Secondary/Exploratory questions:  
1.  
2.  
3.  
Does adjuvant treatment with pramipexole lead to 
improvement in General Depression symptoms, anxiety 
symptoms, sleep, apathy and fatigue?   
Does adjunctive treatment with pramipexole lead to 
increased activity in the brain's reward system?   Is such a 
change linked to clinical efficacy?   
Is high-dose treatment with pramipexole a tolerable 
treatment in terms of side effects?    
Variables  
Primary Variable(s): Total score DARS.  
Secondary variable/variables:  Total score Montgomery-Åsberg 
Depression Rating Scale (MADRS), BOLD signal at MID-task 
(fMRI), rating scales related to sleep problems, apathy, fatigue and 
anxiety. AE (Adverse Medical Event).   
Investigational drug/treatment  
Pramipexole prolonged-release tablet, 0.375 mg to 4.5 mg salt/day 
for 10 weeks (individually varying dose based on efficacy and side 
effects titrated during these weeks)   

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Study population  
Inclusion (not exhaustive list): Age between 18 years and 75 years.
Diagnosis of unipolar depressive episode, bipolar disorder in 
depressive phase or dysthymia. Moderate to severe depression but 
with pronounced symptoms of anhedonia. To be able to participate, 
you must have an ongoing stable  treatment  
with at least  an 
antidepressant/mood stabilizer for at least 4 weeks. 
Exclusion (not exhaustive list): Current pregnancy, breastfeeding 
or planned  pregnancy.  High  suicidal.  Substance abuse. 
Psychotic disorder. Compulsory treatment (LPT). Impulse control 
disorder. Diagnosis of moderate/severe renal failure or severe 
cardiovascular disease. Recently started psychotherapy. Ongoing 
ECT treatment. 
Study design  
Proof of concept study, in which fifteen research subjects are 
included and receive study treatment (no placebo or control group 
occurs). All included research subjects will also be asked to 
participate in the substudy for fMRI examination before and after 10
weeks of treatment with pramipexole. 
Timetable  
Study start: 1 September 2019   
Study end: 1 December 2020.  
Statistical considerations  
The objective of the study is to demonstrate feasibility (proof of 
concept) and we hope to generate preliminary data that will form the
basis for a larger, definitive, randomized controlled trial. 
Specifically, we are interested in investigating: i) can we pick up a 
signal in our material that pramipexole has an anti-anhedonic effect 
in this study population,  (ii) if the treatment doses we proposes are 
reasonable: treatment effect versus side effects, iii) what the 
distribution looks like for DARS before and after treatment in order 
to optimize future dimension calculations. 

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Method description 
Patients will be recruited from outpatient psychiatric clinics or 
inpatient wards. Those who meet the inclusion criteria and none of 
the exclusion criteria will, at the screening visit, undergo a baseline 
assessment including self-report rating scales and blood sampling 
for inflammatory markers (CRP, IL-6, TNF-alpha, white blood 
cells). 
Participants who also consent to the substudy will undergo an fMRI 
examination of the brain’s reward system (MID task). Thereafter, 
study treatment will begin according to the protocol, with dose 
escalation once weekly until treatment effect, maximum dose, or 
intolerable side effects occur. In the event of intolerable side effects, 
the participant will return to the last tolerable dose. A new attempt at 
dose escalation may be made after seven days, up to a maximum of 
two attempts. If serious adverse events occur, the medication will be 
tapered off. 
After ten weeks of pramipexole treatment, a final visit will be 
conducted including new assessment with self-rating scales and 
blood samples as at baseline visits (including new fMRI 
examination for those participating in the substudy).   
Financing  
The study is financed by funds from ALF, the Söderström-Königska
Foundation, SUS Donations and Foundation and the Royal 
Physiographic Society in Lund.    

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6 STUDY FLOW CHART  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7 BACKROUND AND RATIONALE   
Affective disorders are psychiatric syndromes whose main symptoms are changes in affectation or 
mood. Examples of such disorders are major depression (unipolar depression), bipolar disorder and 
Dysthymia. Today's treatment methods for mood disorders are often inadequate. From the start of drug 
treatment, it usually takes a few weeks before the treatment effect becomes noticeable, even though 
any side effects often occur earlier1. In addition, a large proportion of patients do not respond at all to drug treatment 
despite several treatment attempts, and many of those who respond to the treatment have severe and function-limiting residual 
symptoms in the form of, for example, anhedonia and lack of motivation2. It is estimated that up to a third of patients 
with depression do not reach remission despite repeated treatment attempts with different drugs3.  
One reason for this is that the diagnostic criteria in manuals and systems such as DSM-5 and ICD-10 do 
not consider the biological causes of the diseases. To better study depression and other affective 
disorders, psychiatric syndromes can be divided into so-called endophenotypes4, i.e. characteristic 
features (in this case, symptoms) with a clear biological correlation that can occur across the diagnostic 
boundaries and vary within the same diagnosis. In affective disorders, anhedonia has been shown to be 
such an endophenotype5. 
Anhedonia - the inability to feel pleasure or reduced will/"drive" to seek pleasure - is associated with 
affective disorders, but also other psychiatric illnesses such as substance addiction and schizophrenia6. 
Anhedonia is found in 20-40% of all cases of major depression and is a risk factor for developing 
depression with more severe symptoms, longer disease course, treatment resistance and suffering from 
relapse in depression7. Currently, there is no effective and/or specific treatment for the symptoms of 
anhedonia. The onset of anhedonia is thought to be due to dysfunction in the brain's reward system8. 
An important structure in the brain's reward system is the accumbens nucleus (NAc). fMRI scans have 
shown an increased neural activity in NAc in healthy individuals with an expectation of receiving a 
reward; In patients with depression and anhedonia symptoms, the corresponding activity is reduced9. 
In NAc, there are neurons that express the dopaminergic receptor D310. The D3 receptor is considered 
a potential target for the treatment of anhedonia and in animal studies antidepressant effects of D3 
receptor agonists have been demonstrated11.  Most of today's drug treatments for depression affect 
dopaminergic neurotransmission, such as monoamine oxidase inhibitors (MAOIs) and bupropion, 
but none of these act as D3 receptor agonists. 
Anhedonia and similar symptoms have also been associated with increased systemic inflammation12.  
For example, depressed patients with increased levels of inflammation markers in the blood have 
reduced connectivity ("communication") between the reward system and other parts of the brain13. 
Several studies have also shown that inflammation affects dopamine metabolism in the brain, and 
patients with concomitant low-grade systemic inflammation and depression respond better to 
bupropion (which increases dopamine in the synapses) compared to other patients with depression 
without increased inflammation14.  Thus, drugs that affect dopaminergic nerve transmission are likely to 
provide better treatment efficacy in depressed patients with signs of systemic inflammation compared 
to patients with depression as a whole. 
Pramipexole is a selective D3 receptor agonist which is primarily used as a treatment for Parkinson's 
disease (PS) and Willis-Ekbom disease (Restless Legs syndrome). Patients with PS often suffer from 
depression with anhedonia symptoms and it has been suggested that pramipexole has antidepressant 
effects in these patients by affecting dopaminergic neurotransmission15.  Pramipexole has also been 
investigated in a small, randomized trial in unipolar and bipolar depression16–18. However, the clinical 

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effect has been too small to be widely justify treatment with pramipexole instead of usual 
antidepressants that have fewer side effects. However, in these studies, relatively low doses of 
pramipexole (an average of 1.0 mg) have been used when treating with pramipexole between 0.375 
and 4.5 mg in Parkinson's disease. The American Journal of Psychiatry recently published a clinical 
review of patients with bipolar or unipolar therapy-refractory depression treated with pramipexole as 
adjunctive therapy. Interestingly, 76% reported an improvement that persisted up to 16 months after 
the end of treatment with an average dose of 2.5 mg pramipexole19. These results are promising 
because the patients in the study had a high degree of therapy resistance (several had not responded 
to ECT, for example), but the study was uncontrolled and took place within "clinical routine". Thus, well-
controlled and systematic studies are needed before pramipexole can be recommended in the clinic. 
In this pilot study, we want to test the efficacy and tolerability of pramipexole in the higher dose range 
(> 1.5 mg, max 4.5 mg salt) in patients with depression and with significant anhedonia symptoms despite 
usual treatment.   The results of the study will form the basis for designing a larger placebo-controlled 
randomized trial. We also want to test the conditions for an fMRI scan before and after treatment to be 
able to demonstrate ”target engagement”. The aim of this is to eventually find biomarkers that can 
predict the treatment response of pramipexole. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8  
 
 
 
 
 
RISKS AND BENEFITS
Affective disorders are associated with increased mortality in the form of increased suicide risk, but 
there is also increased mortality from other diseases such as cardiovascular diseases20. The WHO 
considers depression to be the main cause of disability in the world, and as many as one in four Swedes 
are at risk of suffering from depression requiring treatment at some point in their lives21. Given the 
often-long duration of the disease, this means severe personal suffering and great costs for society. 
Affective disorders with anhedonia symptoms have been associated with more severe depressive 
symptoms, more relapses, and are also particularly strongly linked to suicide22. There is also a high risk 
that the symptoms of anhedonia will persist after the depression has otherwise improved, and there is 
currently no effective treatment that specifically targets anhedonia. There is therefore a great need in 
this population (affective disorder with anhedonia) to find effective treatment. 
Treatment with pramipexole may cause dose-dependent side effects such as nausea, vomiting, 
orthostatic hypotension, headache and dizziness. In the elderly after long-term treatment, motor 
disorders, hallucinations, delusions, confusion, mania (rare) and disturbed impulse control may develop 
in severe cases, but this is less common23. The risk of this is considered to be lower with shorter 
treatment times and with the use of prolonged-release drugs (as in the current study).  Previous 
psychosis or impulse control disorder are examples of exclusion criteria in our study. In addition to 
unipolar depression and dysthymia, we will also include patients with bipolar disorder in the depressive 
phase in our study. A review of the literature has shown that the proportion of patients who make a 
switch from depression to a manic state during treatment with pramipexole is comparable (or even 
lower) to those who receive placebo24.  Unlike other dopamine receptor agonists, pramipexole can 
induce somnolence (especially at doses above 1.5 mg/day according to FASS) and in rare cases, patients 
have fallen asleep without warning23. Therefore, patients affected by somnolence are instructed to 
refrain from driving and using machines until this side effect has been resolved. According to FASS, 
pramipexole is not contraindicated in any specific disease, in the treatment of Parkinson's disease the 
dose should be reduced in case of concomitant renal impairment (pramipexole is eliminated by the 
kidneys). Renal failure is another example of exclusion criterion in our study. Caution should also be 
exercised in patients with psychotic conditions and concomitant administration of antipsychotic 
medicinal products should be avoided. 
Pramipexole is not indicated for the treatment of anhedonia symptoms and will be administered in this 
study mainly according to the Summary of Product Characteristics (SmPC) for the treatment of 
Parkinson's disease (maximum dose 4.5 mg of salt/day). This is also what has been done in previous 
clinical studies on depressed patients16,18,25. However, in these studies, pramipexole doses above 4.5 mg 
have also been treated16,19. As this increases the likelihood of neuropsychiatric side effects23 and is not 
an approved dose range in Sweden, this does not occur in this study. The study population consists of 
adults who are able to give informed consent.  The drug trial thus does not entail a major risk for 
research subjects, in which case an external safety committee is not considered justified. Adverse 
reactions are followed up with regular weekly contacts (bi-weekly telephone contact and bi-weekly 
physical visit) and are systematically recorded within the framework of the study.   
The risk of severe adverse events is very small with dose ranges below 4.5 mg/day, which has been 
confirmed by several previous clinical studies with pramipexole in depressed patients19. Thus, the 
potential benefit of this pilot study, to demonstrate that this treatment is a feasible and tolerable 
intervention for depression with pronounced anhedonia symptoms, is greater than the risks for the 
included patients as it can lead to a successful treatment of the symptom of anhedonia in the future and 
increase the conditions for individual-based treatment.    
 

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9 RESEARCH QUESTIONS   
The aim of the project is to treat patients with mood disorders and anhedonia symptoms with 
pramipexole as an adjunct to usual treatment. This open-label pilot study is intended as proof of concept 
(PoC) and we hope to obtain preliminary data that can form the basis for a larger, more definitive, 
placebo-controlled study.  We evaluate dosing ranges to achieve sufficient treatment effect without 
obtaining intolerable side effects. According to the literature, this should be an average dose of about 
2.5 mg/day but is expected to vary between individuals. For example, it is known that D3 receptors vary 
with age (fewer at older age) and that older individuals tolerate and need higher dosages to achieve 
treatment effect. Several previous clinical studies with pramipexole have, like this study, used variable 
and flexible dosage.    
Blood samples are taken before and after treatment for analysis of inflammatory markers in order to 
investigate whether these can predict treatment response.  We also want to investigate how the 
function of the brain's reward system is linked to anhedonia and treatment response. To this end, an 
fMRI (MID-task: test of the reward system) is planned to be performed before and after treatment with 
pramipexole (not mandatory to participate in the treatment study). This data will also form the basis 
for future follow-up studies aimed at better understanding the neurobiology behind anhedonia and to 
make prediction analyses of the treatment effect of pramipexole.   
 
9.1 PRIMARY RESEARCH QUESTION AND VARIABLE  
Primary question:   Change in anhedonia symptoms after ten weeks of treatment with 
pramipexole at the highest possible dose (without intolerable side effects, max 4.5 mg).   
 
Primary variable: Dimensional Anhedonia Rating Scale (DARS) score at baseline and week 10 of 
pramipexole treatment.   
 
9.2 SPECIFIC RESEARCH QUESTIONS AND VARIABLES  
Secondary question: Change in depression symptoms after ten weeks of treatment with 
pramipexole? How many respond to pramipexole (responders) and how many reach remission? 
Secondary variable: Total-score MADRS. Response = reduction in MADRS by over 50%, remission = 
MADRS <= 10 after study end.   
9.3 EXPLORATORY RESEARCH QUESTIONS AND VARIABLES   
Exploratory question: What dosage of pramipexole has an effect on anhedonia symptoms without 
causing intolerable side effects? Is there a connection between anhedonia symptoms and systemic 
inflammation in the body? Does pramipexole treatment affect other symptoms associated with 
depression such as fatigue, anxiety, lethargy, and difficulty sleeping? Correlates estimation of 
anhedonia symptoms with DARS with estimation of secondary anhedonia scales (SHAPS, MAP-SR). 
Increases  Task in the brain's reward system after treatment with pramipexole and is this linked 
to clinical efficacy?  Explorative variable: We will evaluate optimal dosing intervals, i.e. lowest and 
highest final dose where the patient had clinical efficacy and at the same time no non-tolerable side 
effects. We will also evaluate the number of dropouts, change in blood levels of inflammatory 
markers, as well as change in anxiety symptoms (GAD-7), fatigue (Fatigue Severity Scale), sleep 

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problems (Insomnia Severity Index), and apathy (AES). Correlation between Snaith–Hamilton Pleasure 
Scale (SHAPS) and Motivation and Pleasure Scale (MAP-SR) total score compared to DARS total score. 
Difference in BOLD signal in ventral striatum (NAc) during monetary incentive delay task before and 
after pramipexole treatment.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10 STUDY DESIGN   
This is an open-label, PoC pilot study in which patients are supplemented with pramipexole for 10 
weeks. The study is being conducted in Lund, at Psychiatry Skåne, Adult Psychiatry Lund as a single 
center study. The treatment study is supplemented with a sub-study with fMRI examination in research 
subjects who wish to participate in this (not mandatory to be included in the main study).    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11 STUDY POPULATION   
Fifteen research subjects with either unipolar depression, bipolar disorder in depressive phase, or 
dysthymia are recruited to receive pramipexole treatment. All research subjects are asked to 
participate in the substudy (fMRI examination).   Patients from the outpatient clinics and inpatient wards 
at the psychiatry in Lund will be asked if they want to participate in the study by treating physicians. 
Only those who are cared for under the Health and Medical Services Act (i.e. not under compulsory 
care) may be considered for the study. After the patient has been informed of the study and given 
consent, the patient will be invited to screening visits to the doctor responsible for research at the 
research clinic or the research physician visits the patient in the ward where the patient is admitted.  All 
examinations/visits in connection with the study will take place at the adult psychiatry in Lund, while 
the fMRI examination will take place at Skåne University Hospital in Lund.    
Research subjects who meet all inclusion criteria and no exclusion criteria as set out below, may be 
included in this study.   
11.1 ELIGIBILITY CRITERIA 
11.1.1 Inclusion criteria 
1. Age ≥18 years ≤75 years. 
2. Diagnosis of; unipolar depressive episode or bipolar disorder in depressive phase or dysthymia.    
3. Depression symptoms: total score ≥ 18, as measured by the Montgomery-Åsberg Depression Rating 
Scale (MADRS).   
4. Anhedonia symptoms: total score <27, as measured by the Dimensional Anhedonia Rating Scale (DARS). 
(Low score = high level of anhedonia symptoms)   
5. Have an ongoing treatment of at least one antidepressant medication ≥ 4 weeks without a dose 
change.  For patients with bipolar disorder, there must also be ongoing treatment with mood-stabilizing 
drugs.   
6. The research subject has signed informed consent to participate in the study. 
11.1.2 Exclusion criteria 
1. Current pregnancy, breastfeeding or planned pregnancy.   
2. High risk of suicide according to the research physician's overall clinical assessment.   
3. Ongoing substance syndrome (within 12 months).   
4. Diagnosis of psychotic disorder.   
5. Treatment according to LPT.   
6. History of impulse control disorder or a current ADHD diagnosis. The patients are assessed using the 
Problem Gambling Severity Index (PGSI) where ≤3 points are considered to indicate "moderate risk 
gambling" which is grounds for exclusion. PGSI will be estimated during follow-up visits and ≥3 points 
are then reason for discontinuation of the study (with a tapering schedule).  In addition to this, at 
baseline, and at all follow-up visits, we will ask specific questions about impulse control behavior 
related to sex, shopping and food intake. We will use questions from the Questionnaire for Impulsive-
Compulsive Disorders in Parkinson's Disease26   
 
7. Diagnosis of intellectual disability, dementia, or other circumstances that imply difficulty in 
understanding the meaning of participating in the study and giving informed consent.   
8. Diagnosis of renal failure (eGFR <50 mL/min/1.73 m2) or severe cardiovascular disease (specifically 

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symptomatic heart failure NYHA class 2). 
9. Recently started psychotherapy (within 6 weeks) or planning to start such treatment while participating 
in the study.   
10. Ongoing ECT treatment.   
11. Other medical conditions or other concomitant drug therapy (see section 13.5) that the investigators 
believe may affect the evaluable nature of the study or conditions that increase the risk of the trial. For 
example, Parkinson's disease, liver failure, ongoing cancer that has not gone into remission over a year 
ago.   
12. Known or suspected allergy to any active substance or excipient in the drug product included in the 
study.   
13. Participation in other studies.   
14. Other reasons that prevent the research subject's participation, such as the risk that the research 
subject cannot complete the study (lack of compliance).  
11.2 CRITERIA FOR DISCONTINUATION OF STUDY PARTICIPATION  
1.  
2.  
3.  
4.  
Low compliance 
New acute suicidality  
Deterioration by more than 25% on MADRS  
In case of unacceptable side effects such as the development of manic state, impulse control 
disorder, or symptoms of heart failure 
  5.    Pregnancy   
  6.    The research subject may terminate his/her participation in the study at any time without 
incurring any consequences for his/her further treatment.   
Investigators may at any time discontinue a research subject's participation in the study due to, for 
example, unacceptable side effects, deteriorating mental health status, or non-compliance with the 
procedures in the study protocol (see study adherence section 12.8).   
If research subjects discontinue prematurely, a plan will be drawn up for the discontinuation of 
pramipexole (tapering schedule). This is done according to recommendations in FASS but can be 
adapted individually if needed (e.g. withdrawal side effects that lead to slower joint progression).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12 STUDY DESIGN  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit  
Screening  
Baseline 
(last two   
weeks after 
Screening)   
v1, v3, 
v5, v7, 
v9   
+/- 2 
days  
V2, V4, 
V6, V8  
+/-2 
day  
v10 
(termina
tion)  
+/-2 day  
Follow-up 
during   
Tapering 
(v14)   
+/- 2 days  
Informed consent  
X  
Anamnesis  
X  
MINI  
X  
SUAS  
X  
SHAPS  
X  
X  
X  
MAP-SR  
X  
X  
X  
GAD-7  
X  
X  
X  
YMRS  
X  
X  
X  
PGSI  
X  
X  
X  
X  
Insomnia Severity Index  
X  
X  
X  
Fatigue Severity Scale  
X  
X  
X  
Apathy Evaluation Scale  
X  
X  
X  
Physical examination  
X  
Blood pressure control  
X  
X  
X  
Incl./exclusion criteria  
X  
X  
Blood tests  
-hCG  
(if 
female 
of 
childbearing 
potential), eGFR, liver status, 
Hb.   
X  
X  
Inflammation tests (CRP, 
leukocytes, IL-6, TNF-alpha)   
X  
X  
fMRI (sub-study)  
(X)  
(X)  
Distribution of study product  
X  
X  
(X)  
MADRS  
X  
X  
X  
X  
DARS  
X  
X  
X  
X  
Telephone contact  
X  
X  
Incidents (AEs)  
X  
X  
X  
X  

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12.1 RECRUITMENT/SCREENING   
Physicians and nursing staff at general psychiatric clinics and inpatient wards (Region Skåne) are 
informed about the study and its inclusion criteria. Patients are asked to participate in the study. We 
will also advertise research subjects. Contact is made with the physician responsible for the patient 
(PAL) to ensure that he or she is prepared to possibly take responsibility for tapering or continued 
treatment with pramipexole after the end of the study (tapering can also take place within the 
framework of the study). The research subject is contacted for booking of screening visits that take place 
at the research clinic. During the visit, anamnesis is recapitulated, somatic diseases, ongoing drug 
treatment and psychiatric status is performed.  Clinical suicide risk assessment is based on psychiatric 
status and with the help of Suicide Assessment Scale (SUAS)27.  In Mini International Neuropsychiatric 
Interview (MINI)28 is done for the purpose of confirming (or rediagnosing) psychiatric diagnoses. 
Assessment of symptoms is made using the MADRS rating scales29 (depression symptoms) and DARS30   
(anhedonia symptoms).   Inclusion and exclusion criteria are systematically assessed and the research 
subject's initials and year of birth as well as the time of screening-visits are documented (screening- log). 
Each research subject is identified by a unique number (enrollment log). The research subject must provide a blood sample in 
connection with the screening visit (-hCG [if woman of childbearing potential], eGFR, liver status and Hb). 
These samples must be checked before a baseline visit can be considered. The research subject will also 
provide blood samples in connection with the baseline visit for analysis of inflammatory markers (CRP, 
leukocytes, IL-6 and TNF-alpha). No biological samples are collected for later analysis. A clinical control 
of status and pulmonary status is performed (including anamnestic questions with a focus on heart 
disease and auscultation of COR/pulm and blood pressure), and a note is written in the research 
subject's medical record. If the research subject is to participate in an fMRI examination, information 
about the procedure is distributed.   Before the baseline visit has been made, it is ensured that the blood 
test results (of hCG, eGFR, liver status and Hb) are assessed and cancel the visit if these are abnormal 
(referral to the appropriate health care provider for further investigation/action is then sent if 
necessary).   
12.2 PROCESS FOR OBTAINING INFORMED CONSENT   
During the screening visit, before reviewing the medical history and inclusion and exclusion criteria, the 
research subject is informed orally about what it means to be part of the study. The information is then 
distributed on paper together with a signature form. The research subject is then allowed to read 
through the information in peace and quiet. The form is then signed and in connection with that, the 
research subject is again informed that it is possible to discontinue the study throughout the study and 
that they will then receive help with tapering off pramipexole if needed. Ethical aspects of processes 
that deviate from normal practice/statutory statutes are described in section 20.   
12.3 PRIOR TO STUDY TREATMENT - BASELINE   
In connection with the baseline visit, blood samples are taken for TNF-alpha, IL-6, CRP and Leukocytes. 
New estimation with MADRS and DARS is performed and with   Generalized   Anxiety   Disorder   7   scale   
(GAD-7; anxiety symptoms), Insomnia Severity Index31 (sleep problems), Fatigue Severity Scale32 (fatigue 
symptoms), Apathy Evaluation Scale33 (AES; apathy), Snaith-Hamilton Pleasure Scale34 (SHAPS) The 
Motivation and Pleasure Scale (MAP-SR)35 (anhedonia symptoms), and with the Young Mania Rating 
Scale (YMRS) (manic symptoms)36.   Study drugs will be dispensed, and the study participant will begin 
treatment during the day (before bedtime) with the up-titration schedule described in section 13.3. A 
diary for dosage is handed out and the patient is instructed to bring this filled in at the next visit.  On 
the same day as the start of pramipexole treatment, an fMRI examination is performed for the research 
subjects as Participating in Sub-studies. On  X-ray department Ensures that there are no contraindications 

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to fMRI (no magnetic implants, normal renal value). Execution of fMRI examination is described in section 
26.1.  The research subject spends approximately one hour in the scanner and receives compensation 
for participation after the survey (see section 20.5).
 
12.4 ALLOCATION OF TREATMENT   
Study participants are assigned a generic version of pramipexole (Pramipexole Orion, see section 13).    
12.5 DURING TREATMENT   
Every two weeks during the study, the research subject is called to the research clinic to discuss up-
titration and side effects as well as new assessment with MADRS and DARS. Blood pressure control is 
performed. A review of the dosing diary and assessment of compliance is sufficient for continued 
participation in the study (number of days of treatment completed, correct dosage, possible change of 
other antidepressant/mood stabilizing drugs). Every two weeks (between physical visits), telephone 
contact is made with the research subjects to check the up-titration status and any side effects. In 
case side effects develop between Visits/telephone contacts the research subject is asked to report this 
directly. The strategy if side effects occur is to go back to the last tolerable dose and wait seven days 
before re-attempting to increase (see section 13 for details).    
12.6 FINAL VISIT    
After ten weeks, a final visit is made.  New blood samples of inflammation markers are taken in the 
morning, and a new fMRI scan is performed on the research subjects participating in the substudy. The 
highest tolerable dose of pramipexole is noted and new estimation with MADRS and DARS is performed. 
A tapering schedule is drawn up if necessary.    
12.7 IN CASE OF EARLY DISCONTINUATION OF STUDY PARTICIPATION   
If the research subject wishes to discontinue the study voluntarily or if it is deemed inappropriate to 
continue (e.g. lack of compliance, unacceptable side effects, deterioration of mental health), the 
research subject is offered a new visit or telephone contact to, among other things, establish a de-
escalation schedule. Too rapid discontinuation of pramipexole increases the risk of withdrawal side 
effects in the form of e.g. apathy, anxiety, depression, fatigue, sweating and pain. When tapering 
becomes relevant, this will be done according to the structure of FASS (vg, see 13.3 below). The research 
subject is asked if the collected data (from fMRI examination) can continue to be stored and analyzed.  
Premature discontinuation is recorded, and significant and/or serious incidents are followed up after 
four weeks until the investigator deems it completed or after two attempts of contact without result.    
12.8 COMPLIANCE    
The requirement for study compliance is that the research subject participates in screening, baseline 
and final visits and taking pramipexole over 75% of the days prescribed regardless of dosage. Every other 
week, the research subject is questioned about the number of tablets taken (control of dosage diary).  
Investigators may also terminate the subject's participation if the intake of pramipexole is exceeded. 
 
 
 
   
 
 
 
 
 

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13 STUDY DRUG   
13.1 INVESTIGATIONAL MEDICINAL PRODUCTS   
In the study, the investigational medicine contains the active substance pramipexole.  In Sweden, it was 
previously marketed under the name Sifrol but is now available in several generic versions. The dosage 
of pramipexole can be stated either as a base or as salt. In FASS, it is first and foremost the dosage as a 
base that is stated and the corresponding concentration in salt is given in parentheses. This protocol 
specifies dosage in salt form to be consistent with dosage indicated in the literature and abroad. In the 
diary and patient information for study participants, the dose is stated in base, as is stated on the 
medicine package and in the FASS.   
Pramipexole is approved in the EU and is indicated as a symptomatic treatment of idiopathic Parkinson's 
disease, alone (without levodopa) or in combination with levodopa, in the maximum dose of 4.5 mg of 
salt.  Pramipexole is also indicated as a symptomatic treatment of moderately to severely idiopathic 
restless legs syndrome in doses up to 0.75 mg of salt. Both apply to adults and not to children.    
Pramipexole has a purely antidepressant effect (in addition to the effect on the underlying disease) in 
patients with Parkinson's disease, according to clinical studies.  It has also been shown to reduce 
anhedonia symptoms in these patients37.  However, pramipexole has no approved indication for the 
treatment of mood disorders. In this study, the research subjects will reach a maximum dose of 4.5 mg 
of salt/day that is already approved for the treatment of Parkinson's disease.   
Common Side Effects According to FASS (Indication Parkinson's Disease):   
Very common (≥ 1/10): Somnolence, Dizziness, Dyskinesia and nausea.   
Common (≥ 1/100, < 1/10): Insomnia, Hallucinations, Abnormal dreams, Confusion,   
Behavioral symptoms of disturbed impulse control and compulsive behavior, Headache, Visual 
impairment incl. diplopia, blurred vision and impaired visual acuity, Hypotension, Constipation, 
Vomiting, Fatigue, Peripheral oedema, Weight loss incl. decreased appetite.   
13.2. HANDLING AND LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS   
The investigational medicine is ordered from pharmacies that also carry out labelling. The medicine is 
then distributed in connection with the visits. In the study, prolonged-release tablets manufactured by 
Orion Pharma are used in strengths (salt) 0.375 mg, 0.75 mg, 1.5 mg, and 3 mg.   
13.2.1 Labelling of Investigational Medicinal Products   
The specific labelling of the investigational drug will take place in accordance with the Medical 
Products Agency's regulations.   
13.2.2 Traceability of Investigational Medicinal Products   
We use the drug accountability log and patients note the intake of drugs in the diary. Leftover medicines 
are returned to pharmacies.    
13.2.3 Storage of Investigational Medicinal Products   
Storage takes place in a locked cabinet, room temperature, at a nurse's office at the research unit.   
13.3 DOSAGE AND ADMINISTRATION OF MEDICINAL PRODUCTS   
The study is based on the hypothesis that it is necessary to reach a high daily dose of pramipexole as 
possible to achieve the expected effects (reduced anhedonia) reported in other studies16, 19. Thus, in the 
event of intolerable side effects, one will return to a lower dosage and make a new attempt at a dose 

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increase at a later time (side effects such as nausea, headache, etc. usually disappear after a week).    
The study uses prolonged-release tablets that are taken once a day. In a phase I study, the minimum 
and maximum plasma concentrations and exposure were equivalent to the same daily dose of 
pramipexole prolonged-release tablets given once daily and pramipexole tablets given three times daily. 
Once daily administration of pramipexole prolonged-release tablets cause fewer fluctuations in 
pramipexole plasma concentrations over 24 hours compared to three times daily administration of 
pramipexole immediate-release tablets.    
Up titration takes place according to FASS, that is:    
Week 1: 1 tablet in strength 0.375mg for 7 days - daily dose 0.375mg    
Week 2: 1 tablet in strength 0.75mg for 7 days - daily dose 0.75mg    
Week 3: 1 tablet in strength 1.5 mg for 7 days - daily dose 1.5 mg    
Week 4: 1 tablet in strength 1.5 mg and 1 tablet in strength 0.75 mg for 7 days - daily dose 2.25 mg    
Week 5: 1 tablet in strength 3 mg for 7 days - daily dose 3 mg    
 
After that, we will make a further increase of 0.75 mg every seven days up to a maximum dosage of 
4.5 mg, depending on treatment response and side effects (see below). 
 
The tablets are usually taken at night if the research subject does not have sleep problems.  If non-
tolerable side effects occur in connection with an increase in dose, the research subject is encouraged 
to notify this and return to the dosage that did not cause side effects. After that, wait another seven 
days before a new attempt at dose increase occurs. This is done on a maximum of two occasions before 
giving up attempts to reach a higher dosage (treatment continues with the lower dosage if possible). An 
exception to this strategy is if the study participant experiences side effects in the form of impulse 
control disorder (e.g.  pathological gambling addiction or compulsive buying behavior), manic state, or 
symptoms of heart failure. If such a situation arise, pramipexole will be tapered off and discontinued. 
Study participants will be assessed with YMRS at baseline, week 2, week 4, week 6, week 8 as well as at 
week 10 to evaluate any manic symptoms.    
The total duration of treatment is ten weeks before an evaluation of efficacy is made and a decision is 
made on continued treatment or discontinuation (referral is sent to PAL, which is responsible for 
continued treatment with pramipexole).  If the research subject during the study shows a 50% decrease 
on MADRS or a 50% increase on DARS (=response), further dose increase is stopped, and the research 
subject then remains on this dose for the rest of the study. Control of compliance This is done by asking 
the research subject to bring the remaining tablets (and dosage diary) to the evaluation visits every two 
weeks for control counting of the number of tablets.    
Pramipexole treatment must not be stopped abruptly due to the risk of dopamine agonist withdrawal 
syndrome (DAWS) with symptoms such as depression, anhedonia, apathy, anxiety, sleep disturbances, 
and others.  The study participant is carefully informed about this.  If discontinuation of the drug 
becomes necessary, this will be done gradually as instructed in FASS: The pramipexole dose is gradually 
reduced by 0.75 mg of salt per day until the daily dose is reduced to 0.75 mg of salt. The dose should 
then be reduced by 0.375 mg of salt per day. The patient is instructed to report any withdrawal side 
effects and then the dose reduction can be individualized to counter them.    
 
 
 
 
 
 

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13.4. NON-INVESTIGATIONAL MEDICINAL PRODUCTS   
The research subject should be on a stable dosage for at least four weeks prior to the start of treatment 
(not ongoing dose changes) of at least one antidepressant. People with bipolar disorder should also be 
given a mood stabilizing drug.   
To ensure that any clinical effect is dependent on pramipexole, it is recommended that study 
participants do not alter their ongoing antidepressant or mood stabilizing medication during the study.  
If the investigator, PAL or the patient himself assesses that the clinical condition nevertheless requires an 
adjustment of standing medication, this should of course be done. Nevertheless, the study participant can 
continue with pramipexole as planned, the change is noted in the patient's study log, and this is taken into 
account in the data analysis.    
 
 
13.5 CONCOMITANT MEDICATION   
Other drugs prescribed by the research subjects are managed as usual through their respective clinics.  
All concomitant medication is allowed while the research subjects are included in the study, except for 
those drugs that fall under exclusion criterion no. 11, i.e.:   
(i) ongoing treatment with medicinal products that affect plasma levels of pramipexole; For example, 
cimetidine, amantadine, mexilepine, zidovudine, cisplatin, quinine and procainamide.    
(ii) ongoing treatment with medicinal products that have a similar or antagonistic mechanism of action 
to pramipexole; For example, MAOIs, levodopa, other dopamine agonists, metoclopramide 
(Primperan), buspirone; This also applies to central stimulants such as methylphenidate and 
amphetamines (not caffeine).    
(iii) ongoing treatment with neuroleptics; For example, olanzapine, haloperidol, risperidone, clozapine, 
aripiprazole, quetiapine (Seroquel).   
After a wash-out of > 14 days of all drugs, a patient can be included in the study.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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14 METHODS FOR COLLECTING STUDY VARIABLES   
The study variables are collected using estimation forms, routine clinical analysis of blood samples and 
with fMRI examination.   
14.1 EFFICACY VARIABLES  
Total score DARS (primary variable) and exploratory variables such as total score MADRS, SHAPS, MAP- 
SR,  GAD-7,  AES,  Fatigue  Severity  Scale  and  Insomnia  Severity  Index gathered in a self-
assessment questionnaire (validation of Swedish translation of DARS is in progress) at  screening-visit baseline-
visits and every other week for 10 weeks in connection with visit at the research clinic (a total of six occasions; 
MADRS and DARS on seven occasions).    
Blood inflammation parameters (CRP, IL-6, TNF-alpha, and leukocytes) are collected at baseline and 
final visits. Other exploratory variables are collected during the fMRI examination.   
14.2 SAFETY AND TOLERABILITY VARIABLES   
14.2.1 Laboratory variables  
Routine laboratory tests (blood tests) consist of eGFR, liver status (ASAT, ALAT, GT, ALP), Hb value and 
-hCG and are taken between screening visits and baseline visits and at the final visits. 
Abnormal/unexpected/abnormal metrics after screening and termination visits are recorded and 
reported as incidents in the study. (see paragraph 15.5 below).   
14.2.2. Vital metrics    
Heart and lung status is performed according to the clinic's standard routine at screening visits.  This 
includes anamnestic questions  with direction against heart disease and  auscultation 
of 
Cor/pulm. 
Blood pressure control is performed according to the clinic's standard routine at screening visits, v2, v4, v6, 
v8 and final visit (v10).  Abnormal/unexpected/abnormal vital signs are recorded and reported as incidents 
in the study. (see paragraph 15.5 below).   
14.2.3. Tolerability variables   
Adverse reactions to pramipexole treatment are collected in connection with visits (biweekly physical 
visit and biweekly telephone contact).  If adverse reactions develop between two visits, the research 
subject is asked to report this, and the strategy is usually to go back to the last tolerable dose and wait 
7 days before making a new attempt at elevation (see section 13.3 for details).    
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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15 SECURITY MONITORING AND REPORTING  
15.1 DEFINITION OF INCIDENT   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15.2 SAFETY INFORMATION   
The Summary of Product Characteristics (SmPC) of pramipexole prolonged-release tablet (Orion 
Pharma) is used for the assessment of the relationship between the event and the medicine and the 
assessment of a suspected unexpected serious event (SUSAR).   
15.3 ASSESSMENT OF SEVERITY  
Mild: short-term/transient symptoms that do not affect the subject's daily activities.   
Moderate: tangible/obvious symptoms that to some extent affect the research subject's daily 
activities.  
Severe: symptoms that significantly affect the subject's daily activities.   
 
 
Term  
Definition  
Incident / Adverse Event 
(AE)   
An undesirable medical event or deterioration of existing conditions in a research 
subject who has received a drug, and which is not necessarily causally related to the 
given treatment.  Examples of incident: symptoms (nausea, somnolence, 
development of hypertension, development of mania.    
Side effect / Adverse 
Reaction (AR)   
An adverse medical event that is judged by a medically competent to have a 
reasonable probability of having a causal relationship with the study drug at any 
dose
Serious Incident /  
Serious Adverse Event 
(SAE)    
An undesirable medical event that meets one or more of the following criteria:   
1. Death.   
2. Life-threatening conditions. The term "life-threatening" refers to an event in 
which the participant was at risk of death at the time of the event. It does not 
refer to an event that hypothetically would have caused death if it were more 
serious.   
3. Requires hospital care or prolongs an already started hospital session.    
4. Causes a permanent or significant disability or disability.    
5. Constitutes a congenital malformation or congenital defect.    
6. Other medically significant event for the research subject that requires an 
intervention to prevent one of the above-mentioned criteria.   
Serious adverse reaction  
Serious Adverse Reaction 
(SAR)   
An adverse medical event that is both serious and is judged by a medically competent 
person to have a reasonable probability of having a causal relationship with the study 
medication.   
SUSAR  
Suspected Unexpected  
Serious Adverse Reaction 
(SUSAR)   
A suspected serious side effect that is unexpected, i.e. the nature and severity of 
which do not correspond to the known information on the medicine as specified in 
the reference safety information (Investigator's Leaflet [IB]) or Summary of Product 
Characteristics).   

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15.4 INCIDENT RELATIONSHIP ASSESSMENT    
Likely: good grounds and sufficient documentation to assume that a relationship between symptoms 
and study drug exists.   
Possible: a possible causal relationship is conceivable and cannot be ignored.   
Unlikely: symptoms that are unlikely to be related to the study drug.   
15.5 REGISTRATION OF INCIDENTS   
At each contact once a week (every other week physical visit and every other week telephone contact), 
the research subject will be asked how he/she has been feeling since the previous contact. The research 
subjects are also informed to report any incident between these visits for discussion of dose changes, 
among other things. Incidents are recorded in the research subject's medical record and in the study's 
CRF.  Registration of difficulty and relationship is only done in CRF.  As a minimum, a description of the 
event (diagnosis or symptoms), start and stop, relationship, severity, and if it is considered serious, 
measures and outcome are recorded for each incident.    
Incidents are followed from the start of treatment until four weeks after the end of visits. If the research 
subject wishes to continue with pramipexole after the end of the study, this is done in consultation with 
the research subject's PAL. In such cases, no dosage decrease takes place, but incidents are followed up 
for four weeks after the final visit via telephone contact until it is completed or after two attempts with 
contact without results.   
All serious incidents will be followed until they are recovered or no longer necessary to be followed.   
15.6 PREGNANCY   
Pregnant women will not be included in the study. Women of childbearing potential must have a 
negative serum -hCG pregnancy test to rule out a pregnancy prior to initiation of treatment.  Blood 
samples are taken between screening visits and baseline visits and at the final visit. Women who become 
pregnant during the study are excluded from the study. The effect of pramipexole on the unborn baby is 
unknown and treatment should be discontinued as early as possible. Clinical data are also lacking for 
pramipexole and breastfeeding, which is why ongoing breastfeeding is an exclusion criterion.    
15.7 REPORTING OF INCIDENTS   
15.7.1 Reporting of Incidents and Adverse Events 
All incidents and adverse events are recorded by the trial site in the CRF during the study. Collected 
incidents and adverse events are reported at the end of the study through the final report to the 
authorities (see below).    
15.7.2 Reporting of Serious Adverse Events and Serious Adverse Reactions (SAEs and SARs)   
All serious incidents must be reported within 24 hours from knowledge to the investigator responsible 
and reported in the CRF. Reporting serious incidents and/or serious adverse reactions to the relevant 
authorities takes place annually through the annual safety report (see below)     
 
 
 
 
 

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15.7.3 Reporting of SUSARs – serious unexpected serious adverse reactions   
A suspicious, serious unexpected adverse reaction to the study drug, SUSAR, that is fatal or life-
threatening is reported to LV and EPM within 7 days of the event being detected. Supplementation of 
the report is sent to the authorities within a maximum of 8 days.   
A suspicious, serious unexpected adverse reaction to the study drug, SUSAR, that is not fatal or life-
threatening is reported to LV and EPM within 15 days of becoming aware of the event. A supplement to 
the report will be sent to the authorities as soon as possible.   
15.8 ANNUAL SAFETY REPORT   
The annual safety report is compiled by investigators and sent to LV and EPM, if EPM so wishes. The 
report summarizes serious incidents that have occurred, as well as a summary assessment of the safety 
of the research subjects who are still included in the trial, and whether the study's benefit-risk 
assessment has changed since the study was approved.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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16 STATISTICAL CONSIDERATIONS  
16.1 POWER CALCULATION    
Fifteen individuals (n = 15) are included in the study to ensure that at least ten individuals complete the 
study (the number of dropouts is estimated to be less than one-third). No clinical study has previously 
used DARS as a primary efficacy variable, but during the development of DARS, the mean standard 
deviation (SD) was 13.73 when estimating depressed patients29. Power calculation with 10 research 
subjects (r = 0.5, α = .05) results in a difference in mean value of 16.6 at power 95% can be detected. 
This corresponds to the research subject estimating one point less on each question in DARS (a total of 
17 questions), which would be a clear clinical improvement.    
16.2 POPULATION   
Complete Analysis Quantity (FAS) is the primary analysis set. The analyses will also be performed on 
per protocol amount (PPS).    
16.3 STATISTICAL ANALYSIS OF PRIMARY, SECONDARY AND EXPLORATORY VARIABLES   
All statistical analysis is performed using the IBM SPPS Statistics v24 software. Paired T-test (2-tailed) is 
used to analyze the difference in DARS scores between baseline and after ten weeks of treatment with pramipexole 
(primary variable). Normal distribution is expected based on previous studies. Descriptive analysis is 
performed by response (reduction by at least 50% in MADRS score), remission (MADRS ≤ 10 at study 
end) of depression symptoms (secondary variable), and number of dropouts. Descriptive analysis, mean 
and range, is performed on the dosage of pramipexole at the end of the visit. Of the exploratory 
variables, similar paired T-tests (or equivalent non-parametric method if necessary) are used for the 
analysis of difference in total scores MADRS, SHAPS, MAP-SR, AES, GAD-7, Fatigue Severity Scale and 
Insomnia Severity Index.   
Analyses may also be made on imputed datasets. If values are missing from the measurements over 
time, they will be replaced with the means of adjacent values before and after the missing value or with 
the last observation.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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17 DATA MANAGEMENT   
17.1 DATA FLOW AND PROCESSING   
Data are collected and processed in coded form after the study has ended. Relevant medical record 
data is transferred to the CRF. Data from CRF, self-assessment forms will then be manually transferred 
to an Excel file that is password protected for further entry. A manual check that the correct entry has 
taken place takes place after the study has been completed and is entered as a variable. Data from the 
Excel file is copied to SPSS database files via automatic functions in the program for statistical analysis 
by authorized personnel.   
17.2 CASE REPORT FORM (CRF, DATA COLLECTION DOCUMENTS)   
The data collected in the study will be recorded in a case record form (CRF) in paper form that is prepared 
specifically for recording data for the study in question.  A research person form must be available for 
each research subject and all questions in the research person form must be answered. Questions that 
cannot be answered will be noted with ND=Not done, NA=Not applicable or NK=Not known. Any 
corrections are made by crossing out the incorrect and dating and signing the change and writing the 
correct information next to it.   
The following rating scales will be added as an appendix to the CRF: MINI, SUAS, SHAPS, MAP-SR, AES, 
GAD-7, Insomnia Severity Index, and Fatigue Severity Scale.    
17.3 SOURCE DATA DOCUMENTS   
1.   Patient record: Kept in the Melior data journal program according to clinical procedures and the 
requirements of the   
clinical trial. The minimum level of what must be recorded:   
(i) Name of the examination   
ii) Information that all criteria for inclusion and none for exclusion have been met   
(iii) Date when the patient signed informed consent   
iv) Date when the patient ends or discontinues the study    
(v) Details of diagnosis    
(vi) Data on intake of investigational medicinal products   
(vii) Details of complications   
2. Consent form   
3.   Patient Identification List: Included patients are assigned research numbers in the   
order they are included. The patients' names and personal identity numbers are registered on 
the list in connection with each research number.   
4. Case Report Form (CRF) and rating scales  
17.4 INPUT AND ACCESS TO STUDY DATA AND SOURCE DOCUMENTS 
Data is entered manually into a data file (Excel and SPSS) in accordance with section 17.1 above. The 
data file is password protected, and only authorized personnel have access to the file. All information 
is coded so that no social security numbers, names, initials, addresses, etc. are found in the file. When 
data was collected, each study participant will be given a specific number, and a code list will be 
established. This is kept locked up and saved to be able to check the quality of the studies. The code 
list and source data are kept locked away.  Monitors from Clinical Studies Sweden – Forum South will 
also have access to source data after signing a non-disclosure agreement. All study material is archived 
for 10 years from the time the study report is written and reported to the authorities.    

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18 QUALITY CONTROL AND MONITORING   
Patients are informed via the patient information that monitoring is taking place and that the monitor 
and any control authority have access to medical records. A confidentiality agreement must be 
established between the operations manager, who is formally responsible for the patients' medical 
records, and the monitor. Monitoring of the study is done by clinical studies Sweden – Forum South 
according to the GCP principles. A risk-based monitoring plan is drawn up.   
Monitor has access to CRF, patient records and originals of laboratory data, etc., to ensure source data 
relevant to the study, without compromising patient privacy. Inspection by an authority may be carried 
out.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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19 ARCHIVING   
Investigators have a study binder with relevant content according to ICH GCP Chapter 8"Essential 
documents”. The place of the trial study data, research person identification list, original research subject 
information and obtained consent for the study will be stored inaccessible to unauthorized persons, but so that 
research subjects in the study can be identified by those responsible for the study.    
A complete trial binder, as well as source documents will be archived at least 10 years after the study 
report is written and submitted to LV. Source data in patient record systems is stored and archived in 
accordance with Region Skåne's regulations.   
The Archives Act (1990:782) applies to the archiving of research material. The National Archives' 
regulations and general guidelines on the disposal of documents in the research activities of 
government agencies, RAFS 1999:1, as well as the region's instructions, will be followed.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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20 ETHICAL AND REGULATORY ASPECTS   
The study is carried out in accordance with the current version of the Declaration of Helsinki, ICH GCP 
and applicable international and national regulations. The study can start when written approval from 
EPM, permission from LV and other approvals required by current regulations are available. The 
responsible examiner is responsible for ensuring that the content of the individual documents 
submitted to LV in an application is identical to the content of the corresponding documents when 
applying for approval at EPM. Approval of notification of personal data processing; approval from KVB 
for extraction from medical records for research; registration in the DSF for PUG treatment; and 
approval of the notification to Image and Function Region Skåne must be obtained. Biobank is not 
needed as blood samples are analyzed and destroyed within 6 months after sampling.   
20.1 SIGNIFICANT CHANGES TO THE STUDY   
If essential changes in study implementation or the study protocol (including research subject 
information) is made after approval, an addition "Amendment" be written and sent to EPM and/or LV for 
approval before this change may be implemented (unless performed to prevent a security risk). The 
respective authority information regarding which changes must be applied for and approved by them 
will be followed. A significant change can be, for example, a change in an inclusion/exclusion criteria, a 
change in investigational medicine or if, for example if the principal investigator (the person responsible 
for the applications) is replaced.    
20.2 SERIOUS PROTOCOL DEVIATIONS   
Deviations from trial protocols, GCP and other regulations that in a significant way directly affect, or 
with a high probability would affect, the research subjects in Sweden or the scientific value of the trial 
must be reported immediately within 7 days to LV. It is the responsibility of the investigator responsible 
to assess the consequences of deviations that have occurred, and thus also decide whether LV should 
be informed.   
 Minor deviations that do not affect the integrity or safety of the research subjects, or significantly 
affect the scientific value of the trial, are documented.   
20.3 REPORT ON CLOSING    
Within 90 days after the end of the study (see definition of study completion below), LV and EPM will 
be notified of termination. The Investigator in charge may at any time discontinue a study if there is a 
reason to do so. This may be that the study's benefits no longer outweigh its risks. In such cases, LV and 
EPM must be informed in writing within 7 days.    
20.4 PARTICIPANT INFORMATION AND OBTAINING INFORMED CONSENT    
All patients are carefully informed in advance about the design of the study and about how the study 
will be conducted and evaluated. Each research subject must have understood the explanation of the 
purpose of the study and how the trial is structured and received written and oral information about 
what the expected benefits and risks are.   
Subjects have the opportunity to make their own trade-off between study treatment and therapy given 
according to clinical practice. They are given the opportunity to ask questions about the study before 
consent is given. It appears that the subject's participation is voluntary and that participation can be 
discontinued at any time without deteriorating medical care. The subjects' signatures give consent to 

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participate in the trial, that the monitor and pharmaceutical authorities (possibly foreign) have access 
to the study's source data under confidentiality.   
The investigator (physician) who informed the patient will certify with their signature that the patient 
received (and understood) the information and gave their consent to the study.   
20.5 COMPENSATION FOR PARTICIPATION IN SUB-STUDY   
The research subjects who are also included in the substudy (fMRI examination) receive a compensation 
of SEK 750 for participation plus a maximum of SEK 500 (normally around SEK 250) as "gains" in the 
monetary incentive delay task (MID). SEK 750 is an incentive to participate in the fMRI examination and 
is normal compensation in fMRI studies38. The level is balanced to be sufficient as an incentive for 
participation in the fMRI examination, but not as an incentive to participate in the main study.  SEK 0 to 
500 is an accepted remuneration in the form of "winnings" in the MID test itself and is a necessity for 
the execution as the test examines the activation of the reward system when receiving monetary gains 
(see appendix 25.1).    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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21 TIMEPLAN AND DEFINITION OF STUDY COMPLETION   
The study is expected to start on 1 September 2019 and is expected to be completed by 1 December 
2020 at the latest. End of the trial occurs when the last research subject has completed the last study 
visit and follow-up telephone contact has been made.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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22 INSURANCE   
Study participants are covered by patient insurance (the Patient Injury Act) as the study is carried out 
within the framework of the county council's health and medical care.  Research subjects are insured 
by the Swedish Pharmaceutical Insurance Association (LFF).    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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23 FINANCING   
Funding comes from the Söderström-Königska Foundation (500 000 SEK, SLS-851561); SUS donations 
and foundations (180 000 SEK) and the Royal Physiographic Society in Lund (90 000 SEK).  Principal 
Investigator Daniel Lindqvist also has a grant in the form of ALF Young Researchers, which frees up 
50% research time in the clinical position.   
 
 
 
 
 

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24 REGISTRATION, REPORT AND PUBLICATION 
 
24.1 REGISTRATION   
The protocol of the study is published in the public registry EU Clinical Trial Register (EU CTR), via 
EudraCT application to LV before inclusion of the first research subject.   
 
24.2 DISSEMINATION   
According to the Declaration of Helsinki, study results will be made publicly available as soon as 
possible after the end of the study, and no later than one year after completion, regardless of whether 
the results are positive, negative or neutral via publication and/or public database.   
 
24.3 REPORT AND PUBLICATION   
The study is planned to lead to a scientific article/report intended for an international peer-reviewed 
journal.  
Publications will also form the final report to LV and EPM. Authorship is determined in accordance 
with the guidelines of the International Committee for Medical Journal Editors (ICMJE). All authors 
must contribute to, review, and accept the final publication. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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25 REFERENCE
 
 
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26 APPENDIX   
26.1 fMRI  
The MRI scans are done with a Siemens 3T scanner or with the Philips 7T.  Initially, examinations are 
performed to obtain structural images of the brain as well as diffusion tensor imaging (diffusion tensor 
imaging; DTI). Thereafter, functional connectivity is examined using the so-called Blood-Oxygen Level 
Dependent (BOLD) resting state. These surveys do not require the research subject to be active in the 
camera. Finally, a BOLD fMRI paradigm is performed during a test called the monetary incentive delay 
task (MID), which explores different phases of reward processes and requires active participation of the 
research subject. All examinations are estimated to take a total of less than an hour in the scanner.    
During MID, simpler images are displayed on a screen and the subject is provided with a button box. At 
each examination, the subject is exposed to visual stimuli on 72 occasions. The images consist of a circle, 
square or triangle (Cue) that indicates how much money can be gained or lost (see image below).   
 
 
 
 
 
 
 
 
 
 
 
 
The clue is displayed for 500 ms and is followed by a fixation cross (200 to 2500 ms). After that, the 
target square (160 to 250 ms) is shown, at which point the research subject is instructed to press the 
button as quickly as possible to win money or not to lose money. The time is adjusted during the test 
so that the research subject succeeds around 66% of the time. Feedback is then given on how it went, 
and the total amount of money raised.    
 
 
 
 
 
 
 
 
 
 
 
 

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27 AMENDMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
No  
Date  
Change and cause  
Author and new version 
1  
190617  
Based   on   comments   from   Ethics   committee (and 
because pramipexole can cause impulsive disorders e.g. 
increased gambling as a side-effect), we changed the 
protocol and added to the exclusion criteria nr 6 a new 
scale “Problem Gambling Severity Index”; to ensure the 
exclusion of subject with risk gambling. The rating takes 
place at baseline meetings and during every second week 
during the pramipexole treatment.     
Daniel Lindqvist v1.1