Scopolamine in Bipolar Depression

This is a single-site, randomised, double-blind, placebo-controlled, parallel, phase IIb clinical trial. The primary objective of the SCOPE-BD study is to investigate the efficacy and safety of IV Scopolamine, compared to placebo, in reducing severity of depression in individuals with bipolar disorder who are experiencing a depressive episode of at least moderate severity

Bipolar disorder is a chronic disabling psychiatric disorder characterized by recurrent episodes of mania or hypomania and depression. Bipolar disorder can be separated into bipolar 1 and bipolar 2 disorders with bipolar 1 disorder characterizing individuals who have episodes of mania and depression, and bipolar 2 disorder characterizing individuals who have episodes of depression with periods of hypomania, but not mania. Bipolar disorder has an estimated prevalence of approximately 1% and a roughly equal gender ratio. Current pharmacological treatments for bipolar disorder and in particular for the management of depressive episodes in bipolar disorder remain sub-optimal, with pharmacological strategies employed to date often only partially effective. In addition to the time duration for treatment response, multiple treatment trials are also often required, thus increasing patient discomfort and distress.Consequently, pharmacological mechanisms that potentially alleviate depressive symptomatology in bipolar disorder and ameliorate patient functioning could present an additional pharmacological strategy for the management of bipolar disorder. A number of recent studies have suggested that Scopolamine, a pan muscarinic (M) receptor antagonist can elicit a rapid anti-depressant response in both major depressive disorder (MDD) and bipolar disorder and thus may present a novel therapeutic strategy, particularly for the management of bipolar disorder, in individuals experiencing depressive episodes. No significant adverse effects were noted with treatment with Scopolamine (intravenously) in these studies.

This antidepressant effect has been rapid in effect in studies where administration was by an intravenous (IV) method.Of note, those clinical trials where efficacy has been demonstrated have been undertaken in the same centre (Mood and Anxieties Disorder Program at the National Institute of Mental Health in Bethesda, MD) with the more recent trials of larger numbers from that centre including individuals that participated in the previous clinical trials. Although beneficial effects have been noted for depressive episodes in both MDD and bipolar disorder, the actual numbers of participants with bipolar disorder has been limited.

Fewer studies have utilised other potential modes of administration for Scopolamine. A previous study of intramuscular scopolamine demonstrated no antidepressant effect whilst one trial of oral scopolamine as an augmentation agent demonstrated an antidepressant effect, albeit this study did not demonstrate a rapid-acting effect as demonstrated in the studies of IV Scopolamine and did not include individuals with bipolar disorder. In addition, oral Scopolamine has very limited bioavailability of \~4 %.Trials relating to administration of Scopolamine utilising a transdermal patch for the management of depressive episodes have yet to be published.

This is a single-site, randomised, double-blind, placebo-controlled, parallel, phase IIb clinical trial. The trial will be sponsored by the National University of Ireland (NUI) Galway and the sponsorship role coordinated by the HRB-Clinical Research facility Galway (CRFG). The site will be University Hospital Galway, Galway and the site activities will also be co-ordinated by the CRFG. Participants will be attending the Galway-Roscommon Mental Health Services, including a specialised bipolar clinic in Galway and referred due to experiencing a depressive episode by their treating clinical team; or patients who have previously attended NUI Galway/HRB-CRFG with an interest to participate/or have participated in research and have indicated a willingness to engage in future research; or patients who approach the research group directly requesting participation.

Trial participants will be adults (both male and female) who have bipolar disorder and are experiencing a depressive episode of at least moderate severity. A diagnosis of bipolar disorder (bipolar 1 or 2 disorder) will be determined by interview with the Structured Clinical Interview for DSM-V (SCID-RV) with severity of the depressive episode assessed using the Hamilton Depression Rating Scale (HDRS) (HDRS ≥14 for study inclusion) at screening.

The primary outcome in this study is the change in severity of depressive symptoms as measured on the Hamilton Depression Rating Scale score (HDRS). Allocating 25 participants to each arm will ensure power ≥85% to detect a 50% lower score on the Hamilton Depression Rating Scale score (HDRS) in the Scopolamine group compared to placebo group. This assumes a loss to follow-up of ≤12%. It is also anticipated that approximately 60 participants will need to be recruited to ensure 50 participants are eligible for randomisation after a placebo run-in.

After a screening Visit (Visit 1); at Visit 2, all participants will receive placebo run-in (100mls of Saline IV). The screening visit (Visit 1) and Visit 2 may occur on the same day. Within 7 days of Visit 2, participants will be randomised (Visit 3) to receive either placebo (n=25) or 4 μg/kg Scopolamine (n=25) IV in 100mls of Saline over 15 minutes at Visits 3 (day 0), 4 (days 2-6) and 5 (days 6-10), with at least 2 days between IV infusions (Visits 2, 3, 4 and 5). Two follow-up visits (Visits 6 and 7) will occur at day 15 (+/-5 days) and day 29 (+/- 7 days).There will be at least 2 days between Visits 5 and 6 and 3 days between Visits 6 and 7. Participants randomised to the placebo group will receive one 15-minute infusion of IV saline,repeated over 3 visits (Visit 3, 4 \& 5). The placebo and active comparators will be indistinguishable from each other.

Participants will be randomly assigned to receive either scopolamine or placebo in a 1:1 ratio. Randomly permuted blocks of sizes 4 and 6 will be used to ensure similar numbers of participants in each arm of the trial.

Randomisation will be stratified by the HDRS score at trial entry (a score of \<23 indicating a mild-moderate depressive episode and a score ≥23 indicating a severe depressive episode). A validated randomisation system will be used at Visit 3, (after HDRS and Young Mania Rating Scale (YMRS) are completed) to randomise patients to either arm. This centralised system will ensure allocation concealment; preventing blinded trial staff from knowing which treatment group will be allocated. Blocks of randomly varying length will also reduce the predictability of the allocation sequence.

Effectiveness outcomes will be analysed on an intention-to-treat basis for all participants randomised and with available follow-up data as per their randomised allocation. A per-protocol dataset is not well-defined under multiple treatments, here it could reasonably be defined as those participants who either received at least 1, at least 2 or all 3 IV treatments after randomisation. Sensitivity analyses will thus be performed on the primary outcome to assess efficacy of the treatment compared to placebo by incorporating the original allocation of participants and their level of adherence to treatment. This will involve examining the short term-effect of treatment in a longitudinal model and the overall effect of number of IV treatments received at follow-up visits after the final IV treatment.

For the primary effectiveness analysis of the primary outcome, it is expected that pre-randomisation measurements of the HDRS score will be correlated with the scores obtained at Visit 6 of treatment. The mean scores at Visit 6 will be compared across the study arms using an ANCOVA model. The response variable will be the change in HDRS score from Visit 3 to HDRS at Visit 6 including the HDRS score at Visit 3 as a covariate in the model. The addition of stratifying variables and other variables as covariates will be considered as appropriate and specified in the statistical analysis plan. This analysis will increase the power to detect significant differences between the groups. Inverse probability weighting will be applied to the primary outcome analysis. These weights will be derived based on the inverse of the probability of a patient's data being missing given their pre-randomisation measurements. This will ensure the estimate and inference is more representative of all patients randomised, reducing bias in the estimation of the treatment effect due to participants lost to follow-up and missing data.

Inference regarding the treatment effectiveness will focus on the point estimate, confidence interval and p-value for hypothesis confirmation.

Eligibility Criteria:
Inclusion Criteria:

To be eligible for inclusion, each participant must meet all of the following inclusion criteria at Screening (Visit 1) and must continue to fulfil these criteria at Visit 2 to take part in the trial:

1. Diagnosis of Bipolar Disorder according to Diagnostic Statistics Manual (DSM)-V criteria
2. Experiencing an episode of depression of at least moderate severity at Visit 1 (Screening) and Visit 2 based on clinical interview by a trained clinician and a Hamilton Depression Rating Scale (HDRS) score ≥ 14.
3. ≥ 18 years old at Visit 2 (male or female)
4. In the opinion of the Principal Investigator or Sub Investigator's, be able and willing to provide written informed consent and to comply with the requirements of this study protocol.
5. Written informed consent prior to participating in the study
6. Urea and Electrolytes (U\&Es), Liver Function Tests (LFTs) and Thyroid Function Tests (TFTs) laboratory tests within acceptable ranges in the previous 4 months of the Screening Visit (Visit 1).

   Placebo run-in inclusion criteria at Randomisation visit (Visit 3):
7. In addition to above, participants must be experiencing an episode of depression of at least mild severity (having previously experienced an episode of moderate depression at Visit 2 with HDRS ≥14), based on clinical interview by a trained clinician and a HDRS score of ≥ 8.

Exclusion Criteria:

Participants who meet any one or more of the following exclusion criteria at Screening (Visit 1) or the Visit 2 will not be eligible to take part in the trial:

1. History of other Axis I diagnosis (including Recurrent Depressive Disorder or Psychotic Disorders such as schizo-affective disorder, conditions that can also present with depressive episodes)
2. History in the three months prior to Visit 2 of alcohol dependence syndrome or substance dependence syndrome.
3. Current use of oral steroid at Visit 1
4. A confirmed diagnosis of dementia
5. A diagnosis of intellectual disability (IQ \< 70)
6. Participants with bipolar disorder that are euthymic in the investigators opinion at screening or Visit 2.
7. Participants with bipolar disorder that are hypomanic or manic (Young Mania Rating Scale (YMRS) \> 6) at screening or Visit 2.
8. Presence of an established neurological disorder or other serious demyelinating conditions as determined by the treating physician (e.g. space occupying lesion, multiple sclerosis)
9. Current involuntary detention under the Mental Health Act (MHA) 2001 in an acute psychiatric inpatient unit
10. Severity of Bipolar Disorder is such that participation in a clinical trial is not appropriate because of the risk of imminent self-harm (based on clinical note review and review at screening visit by experienced clinician)
11. A history of an allergic reaction or sensitivity to Scopolamine (Hyoscine Hydrobromide). Participants will be asked at the screening visit about any previous treatment with scopolamine (Hyoscine Hydrobromide) to ascertain any previous allergic reaction or sensitivity to this agent.
12. A clinical diagnosis of narrow angle glaucoma, myasthenia gravis, paralytic ileus,pyloric stenosis, toxic megacolon and acute porphyria.
13. Individuals will be excluded from the study if currently prescribed anticholinergic medications, including Physostigmine, Biperiden and Procyclidine. Individuals will additionally be excluded if currently prescribed Tricyclic Antidepressants which are associated with significant anticholinergic properties (e.g. Amitriptyline and Nortriptyline) that are currently causing the participant to experience anticholinergic side effects (e.g. blurred vision, constipation, urinary retention, cognitive difficulties). No individuals will have anticholinergic medications stopped to allow them enter the trial.
14. Bradycardia \< 50 bpm, tachycardia \> 100bpm or hypotension (systolic BP \<90 and / or diastolic BP \< 60) prior to IV administration of placebo or Scopolamine
15. A recent history in the last 6 months of symptomatic orthostatic hypotension or syncope.
16. Previous participation in this trial. Participation is defined as randomised. Participation in another trial within 3 months prior to Visit 1. Receipt of any investigational medicinal product (IMP) within 3 months prior to Visit 1.
17. Participants concurrently being administered Electroconvulsive Therapy (ECT).
18. Pregnancy, as determined by a positive urine dipstick at Visits 2, 3, 4, 5, positive blood serum result executed at Visit 2 and confirmed prior to infusion at Visit 3 or participants who are actively breastfeeding (female only).
19. Women of child-bearing potential are defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment. Highly effective contraception methods include:

    * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment.
    * Male partner sterilization
    * Combination of any two of the following:

      1. Barrier methods of contraception e.g. Condom
      2. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception
      3. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    * Women who are considered post-menopausal i.e. amenorrhea at least 12 months or undergone hysterectomy/bilateral oophorectomy
20. Any disorder, unwillingness or inability, not covered by any of the other exclusion criteria, which in the investigator's opinion, might jeopardise the participant's safety or compliance with the protocol

    Placebo run-in exclusion criteria at Randomisation visit (Visit 3):
21. In addition to having completed Visit 2, participants must not be experiencing a hypomanic, or manic episode (YMRS \>6).
22. A Serious Adverse Event (SAE) experienced during infusion which required medical intervention and whereby attending physician deemed it inappropriate for the participant to engage in future infusions.