FAQs for Cequel Trial

Many questions can be dealt with by referring to the protocol but clinicians may either not have it to hand or want a quick answer.

1. QUETIAPINE AND METABOLIC SYNDROME/DYSFUNCTION
We recognise concerns about metabolic problems and provide a copy of the appendix from the NICE National Clinical Practice Guideline No. 38 on Bipolar Disorder (2006) which outlines recommended checks for people taking quetiapine. Quetiapine is widely prescribed and there is no reason to anticipate that the adverse effects experienced by trial participants will be worse that those seen in routine practice.


2. EFFICACY OF QUETIAPINE questioned by a clinician
Rationale for using quetiapine is explained in protocol.
We think it justified to use quetiapine, as reasoned in the protocol which has ethical approval, because existing treatment with antidepressants is not ideal (risk of switching and limited efficacy in bipolar depression) . Recommended by NICE.
From the executive summary NICE National Clinical Practice Guideline No. 38 on Bipolar Disorder (2006).


Patients with moderate or severe depressive symptoms
1.4.3.5 For patients with moderate or severe depressive symptoms, prescribers
should normally consider:
● prescribing an SSRI antidepressant (but not paroxetine in pregnant
women), because these are less likely than tricyclic antidepressants to
be associated with switching, or
● adding quetiapine, if the patient is already taking antimanic medication
that is not an antipsychotic

Long term treatment with standard antidepressants is not recommended by NICE because of risk of switching.


3. WHAT WOULD HAPPEN IF HE IDENTIFIED A PATIENT FOR CEQUEL, BUT THEY ARE ALREADY PRESCRIBED LAMOTRIGINE FOR EPILEPSY?
The pt would not be eligible. Exclusion Criteria says "definite indications to lamotrigine". If pt could be prescribed alternative medication for epilepsy then pt could take part.


4.HOW LONG DOES THE SCREENING INTERVIEW TAKE ON AVERAGE?
Depends on how much information the patient has prior to the appointment. In order of 45mins max. Much less for randomisation and follow ups.


5.WHAT WOULD HAPPEN IF A CLINICIAN WAS ON ANNUAL LEAVE WHEN THE 12 WEEK FOLLOW UP IS DUE, IS THERE ANY LEEWAY?
FU must be done between 10-14 weeks following randomisation.


6. CONCERN ABOUT PATIENTS RECEIVING 4 AND 8 WEEK SUPPLY OF MEDICATION IF THEY ARE DEPRESSED AND PRESENT A RISK, WHO WOULD TAKE RESPONSIBILITY?
If they had a CPN then meds could be sent to them to be given to pt on a regular basis. The Investigator would need to decide how best to handle this.


7. CAN INVESTIGATOR STOP OR CHANGE THE DOSE OF QUETIAPINE?
Before the 12-week follow-up: We would encourage investigators not to reduce the dose below 150mg for the first 12 weeks unless there are definite clinical reasons to stop quetiapine or the participant withdraws consent.

After the 12-week follow-up appointment: We would encourage continuation of the randomised dose for as long as possible. However, where symptoms have resolved and/or there are concerns about adverse effect, quetiapine can be prescribed at a lower dose or stopped.


8. "WHAT ARE THE SAFETY REPORTING REQUIREMENTS FOR QUETIAPINE?
Suspected reactions to quetiapine should be treated as adverse events (as for reactions to other concurrent medications).


Explanation:
In CEQUEL, quetiapine is classed as a NIMP (Non-investigational Medicinal Product). Safety reporting responsibilities for NIMPs are outlined in the EU document “Definition of Investigational Medicinal Products (IMPs). Definition of Non Investigational Medicinal Products (NIMPs)” Section 3.3.:

http://ec.europa.eu/enterprise/pharmaceuticals/pharmacos/docs/doc2006/07_2006/def_imp_2006_07_27.pdf

This document refers to Article 2n of the EU directive 2001_20_EC which defines an Adverse Reaction as an “untoward and unintended responses to an investigational medicinal product”. Since, In CEQUEL, quetiapine is not an IMP it is not covered by the EU reporting requirements for ARs. Any adverse reactions to quetiapine that are considered to be serious should therefore be reported as SAEs not SARs "


9.Does combination therapy with quetiapine plus lamotrigine lead to a greater treatment response by 12 weeks than quetiapine monotherapy plus lamotrigine placebo in patients with bipolar depressive disorder?


10.Does adjunctive folic acid lead to a greater treatment response by 12 weeks than folic acid placebo in patients with bipolar depressive disorder?



11.Does combination therapy with quetiapine plus lamotrigine produce superior outcomes to quetiapine monotherapy + lamotrigine placebo at 12 months?


12.Does adjunctive folic acid produce superior outcomes to folic acid placebo at 12 months?


13.Are there important differences in the relative efficacy, safety and tolerability of quetiapine plus lamotrigine versus quetiapine monotherapy + lamotrigine placebo between clinically-defined subgroups of patients?


14.Are there important differences in the relative efficacy, safety and tolerability of folic acid and placebo between genetic (MTHFR C677T and COMT Val158Met) defined subgroups of patients?


15.Does the baseline homocysteine, folate or vitamin B12 status influence response to folic acid?


16.What are the incremental cost, effects and cost-effectiveness of quetiapine plus lamotrigine combination therapy versus quetiapine monotherapy?


17.What are the incremental costs, effects and cost-effectiveness of folic acid versus placebo?


18. Can patients already be on quetiapine?


19. Can patients already be on lamotrigine


20. Do I have to stop antidepressants?


21. Can the patients stay on mood stabilisers?


22. Are patients with schizoaffective disorder eligible?


23. How long does the screening interview take?


24. How do I sign up to become an investigator?


25. Can I change the dose of quetiapine after randomisation?