Clinical Trial to Investigate the Safety and Efficacy of Two Dexamfetamine Sulfate Formulations in Adults With ADHD and Moderate to Severe Depression

Randomized, Placebo-controlled Clinical Trial to Investigate the Safety and Efficacy of Two Dexamfetamine Sulfate Formulations in Adults With ADHD and Moderate to Severe Depression (DEXAD)

The indication of attention-deficit/hyperactivity disorder (ADHD) to be examined often occurs with other psychiatric disorders, and the majority of adults with ADHD have at least one psychiatric comorbidity in their lives. Depression is one of the most common comorbidities in patients with ADHD. The prevalence of comorbid depression in adults with ADHD is estimated to be as high as 50%.

There is evidence that stimulants such as dexamfetamine and methylphenidate lead to an improvement in sustained focused attention, working memory, and a variety of cognitive processes in the prefrontal cortex (PFC). In combination with the pharmacological effects of stimulants, such as the inhibition of monoamine oxidase, the increase in the concentration of noradrenaline in the PFC and dopamine in the striatum, dexamfetamine and methylphenidate could improve the treatment of depression in patients with major depressive disorder and comorbid ADHD.

This clinical trial will evaluate the safety and efficacy of DEX in two different formulations compared to placebo in adults with ADHD and moderate to severe depression. To ensure double blinding of the treatment, placebo will be administered in the form of tablets and capsules.

Inclusion Criteria:

1. Diagnosis of attention deficit / hyperactivity disorder (ADHD) (according to DSM-5 (fifth version of Diagnostic and Statistical Manual of Mental Disorders) or ICD (International Statistical Classification Of Diseases And Related Health Problems) guidelines) which started in childhood (at the age of <12 years)
2. Patient has a minimum ADHS-Diagnostische Checkliste-Q (ADHS-DC) total score of 32 at baseline (Visit (V) 0)
3. Moderate to severe depression according to ICD-10 (depressive episode: Code F32; recurrent depressive disorder: Code F33) and with a Montgomery-Åsberg Depression Rating Scale (MADRS) score of >20 at baseline (V0)
4. CGI-S ≥ 4 at baseline (V0)
5. Patients receiving selective serotonin reuptake inhibitors (SSRIs) or Serotonin-norepinephrine reuptake inhibitors (SNRIs) (stable doses within the last 2 weeks before inclusion) (≤40 mg (es)citalopram, 50-200 mg sertraline, 75 - 300 mg venlafaxine extended release)
6. Male or female patients ≥ 18 years and ≤ 65 at time of enrolment
7. Patients with QTc interval within normal ranges (≤470 ms in males and ≤480 ms in females)
8. Patient is either free of stimulant medication or who, after discussion with his / her treating physician, is able and willing to discontinue the current psychotropic medication(s) for treatment of ADHD symptoms (specifically, methylphenidate, lisdexamfetamine, guanfacine or atomoxetine or any other medication approved for the treatment of ADHD) ) for the duration of the study, as well as is able and willing to discontinue all relevant co-medication according to exclusion criterion no. 20a-s for comorbid conditions during the clinical trial, if applicable
9. Written informed consent and data protection declaration obtained prior to the initiation of any protocol required procedures
10. Willing and able to comply to study procedures and study protocol

Exclusion Criteria:

1. Current or a history of severe co-morbid symptoms such as psychotic symptoms, schizophrenia, bipolar disorders or manic episodes

2. Current or recent history of substance abuse disorder within the last 6 months of clinical trial entry

3. Patients with body mass index (BMI) < 18.5 kg/m² or >35 kg/m²

4. History of serotonin syndrome events

5. History of seizures or use of anticonvulsant medication

6. Any other uncontrolled psychiatric condition that requires medication or may interfere with trial participation

7. Known symptomatic cardiovascular disease including structural abnormalities, moderate and severe hypertension (systolic blood pressure ≥160 mmHg, diastolic blood pressure ≥100 mmHg), heart failure, myocardial infarction, arterial occlusive disease, angina, haemodynamically significant congenital heart disease, cardiomyopathies, potentially life-threatening arrhythmias and channelopathies (diseases caused by ion channel dysfunction)

8. Significant, in the discretion of the investigator, hepatic, gastrointestinal, renal, haematological or oncologic disorder

9. Diagnosis of glaucoma, hyperthyroidism, pheochromocytoma or porphyria

10. Diagnosis or family history of Tourette's syndrome or dystonia

11. Pre-existing cerebrovascular disorders such as cerebral aneurysm, vascular abnormalities including vasculitis or stroke

12. Immunodeficiency disorders (e.g. organ transplantation, Human Immunodeficiency Virus (HIV) infection)

13. Known hypersensitivity to any of the ingredients of the trial medication, e.g. patients with known rare hereditary problems of fructose intolerance

14. Males or females of reproductive potential not willing to use effective contraception (defined as PEARL index <1 - e.g. contraceptive pill, intrauterine device (IUD)) during the study period (Screening to Follow-up)

15. Pregnancy and lactation

16. Participation in another interventional clinical trial during the trial and within the previous 30 days prior to trial start

17. Patients who are institutionalised by court order or regulatory action

18. Patients, who are members of the staff of the trial centre, staff of the sponsor or involved Clinical Research Organisation (CRO), the investigator him- / herself or close relatives of the investigator

19. Legal incapacity and/ or other circumstances rendering the patient unable to understand the nature, scope and possible impact of the clinical trial

20. Current use of and use within the last 2 weeks before inclusion due to possible interactions with stimulants or SSRIs/SNRIs and possible resulting or expected side effects:

    1. Antipsychotics (such as chlorpromazine, haloperidol, thioridazine; except for quetiapine up to 100mg/day)
    2. SSRIs and SNRIs daily doses of >40 mg (es)citalopram, >200 mg sertraline, >300 mg venlafaxine extended release
    3. Monoamine oxidase inhibitors (MAO) inhibitors
    4. tricyclic antidepressants
    5. benzodiazepines (including Z-drugs)
    6. atypical antidepressants (with an exception for daily doses of 100-300 mg trazodone)
    7. Dopamine reuptake inhibitors (special restriction for bupropion)
    8. antiarrhythmics (Class IA and III)
    9. antibiotics (in particular macrolides and fluoroquinolones, linezolid)
    10. opioids
    11. hydroxychloroquine, chloroquine
    12. ketoconazole
    13. acetylsalicylic acid (dose up to 300 mg allowed)
    14. diphenhydramine
    15. apixaban
    16. metoprolol
    17. pregabalin
    18. budesonide / formoterol
    19. albuterol / salbutamol